U.S. patent application number 11/572967 was filed with the patent office on 2008-03-13 for piperidine derivatives as histamine h3 receptor ligands.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to James Folmer, Peter Hamley, Simon Fraser Hunt, Steven Wesolowski.
Application Number | 20080064706 11/572967 |
Document ID | / |
Family ID | 32906883 |
Filed Date | 2008-03-13 |
United States Patent
Application |
20080064706 |
Kind Code |
A1 |
Folmer; James ; et
al. |
March 13, 2008 |
Piperidine Derivatives as Histamine H3 Receptor Ligands
Abstract
Compounds of formula: wherein Ar.sup.1 and Q are as defined in
the specification, as well as salts, enantiomers thereof and
pharmaceutical compositions including the compounds are prepared.
They are useful in therapy, in particular in the treatment of
depression. ##STR1##
Inventors: |
Folmer; James; (Wilmington,
DE) ; Hunt; Simon Fraser; (Leicestershire, GB)
; Hamley; Peter; (Koenigstein, DE) ; Wesolowski;
Steven; (Wilmington, DE) |
Correspondence
Address: |
ASTRA ZENECA PHARMACEUTICALS LP;GLOBAL INTELLECTUAL PROPERTY
1800 CONCORD PIKE
WILMINGTON
DE
19850-5437
US
|
Assignee: |
AstraZeneca AB
SE-151 85
Sodertalje
SE
|
Family ID: |
32906883 |
Appl. No.: |
11/572967 |
Filed: |
July 27, 2005 |
PCT Filed: |
July 27, 2005 |
PCT NO: |
PCT/SE05/01189 |
371 Date: |
January 30, 2007 |
Current U.S.
Class: |
514/253.01 ;
514/315; 514/316; 544/360; 544/364; 546/189; 546/244 |
Current CPC
Class: |
C07D 405/12 20130101;
C07D 417/12 20130101; C07D 471/04 20130101; C07D 471/10 20130101;
C07D 401/14 20130101; A61P 25/24 20180101; C07D 211/58 20130101;
C07D 401/12 20130101 |
Class at
Publication: |
514/253.01 ;
514/315; 514/316; 544/360; 544/364; 546/189; 546/244 |
International
Class: |
A61K 31/4465 20060101
A61K031/4465; A61K 31/496 20060101 A61K031/496; A61P 25/24 20060101
A61P025/24; C07D 211/98 20060101 C07D211/98; C07D 401/12 20060101
C07D401/12; C07D 401/14 20060101 C07D401/14 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 2, 2004 |
SE |
0401971-7 |
Claims
1. A compound of formula I, a pharmaceutically acceptable salt
thereof, diastereomers, enantiomers, or mixtures thereof:
##STR131## wherein Ar.sup.1 is selected from C.sub.6-10aryl and
C.sub.2-9heteroaryl, wherein said C.sub.6-10aryl and
C.sub.2-9heteroaryl are optionally substituted with one or more
groups selected from --R, --NO.sub.2, --OR, --Cl, --Br, --I, --F,
--CF.sub.3, --OCF.sub.3, --C(.dbd.O)R, --C(.dbd.O)OH, --NH.sub.2,
--SH, --NHR, --NR.sub.2, --SR, --SO.sub.3H, --SO.sub.2R,
--SO.sub.2NR, --S(.dbd.O)R, --CN, --OH, --C(.dbd.O)OR,
--C(.dbd.O)NR.sub.2, --NRC(.dbd.O)R, and --NRC(.dbd.O)--OR, wherein
R is, independently, a hydrogen, C.sub.3-6cycloalkyl,
C.sub.3-6heterocyclyl, phenyl, benzyl, C.sub.1-6alkyl or
C.sub.2-6alkenyl and wherein said R is further optionally
substituted with one or more groups selected from methyl, methoxy,
hydroxy and halogen; and Q is a divalent or trivalent group that
connects the carbonyl with Ar.sup.1, wherein said divalent or
trivalent group contains at least one nitrogen, said nitrogen is
directly connected to the carbonyl group of formula I to form an
amide bond therebetween, and said trivalent group is fused with
Ar.sup.1, or Ar.sup.1 is represented by ##STR132## wherein Ar is
selected from phenyl, pyridyl, naphthyl,
1,2,3,4-tetrahydro-naphthyl; thienyl, furyl, thiazolyl,
benzo[1,3]dioxolyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridinyl;
2,3-dihydro-benzo[1,4]dioxinyl; quinolyl; isoquinolyl; indolyl;
pyrroyl, benzotriazolyl; benzoimidazolyl, 2,3-dihydro-benzofuranyl;
2,3-dihydro-isoindol-1-on-yl; benzo[1,2,3]thiadiazolyl,
benzothiazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, and
4H-benzo[1,4]oxazin-3-on-yl; R.sup.1, R.sup.2 and R.sup.3 are
independently selected from --R, --NO.sub.2, --OR, --Cl, --Br, --I,
--F, --CF.sub.3, --C(.dbd.O)R, --C(.dbd.O)OH, --NH.sub.2, --SH,
--NHR, --NR.sub.2, --SR, --SO.sub.3H, --SO.sub.2R, --SO.sub.2NR,
--S(.dbd.O)R, --CN, --OH, C(.dbd.O)OR, --C(.dbd.O)NR.sub.2,
--NRC(.dbd.O)R, and --NRC(.dbd.O)--OR, wherein R is, independently,
a hydrogen, C.sub.5-6cycloalkyl, C.sub.3-5heterocyclyl, phenyl,
benzyl, C.sub.1-4alkyl or C.sub.2-4alkenyl, and wherein said R is
further optionally substituted with one or more groups selected
from methyl, cyano, methoxy, hydroxy and halogen; Q is selected
from: ##STR133## ##STR134## or Q may be a trivalent group such as
##STR135## which is fused with Ar.sup.1, wherein Ar.sup.1 is a
divalent aromatic group such as 1,2-phenylene.
2. A compound according to claim 1, wherein Ar.sup.1 is represented
by ##STR136## wherein Ar is selected from phenyl, pyridyl,
naphthyl, 1,2,3,4-tetrahydro-naphthyl; thienyl, furyl, thiazolyl,
benzo[1,3]dioxolyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridinyl;
2,3-dihydro-benzo[1,4]dioxinyl; quinolyl; isoquinolyl; indolyl;
pyrroyl, benzotriazolyl; benzoimidazolyl, 2,3-dihydro-benzofuranyl;
2,3-dihydro-isoindol-1-on-yl; benzo[1,2,3]thiadiazolyl,
benzothiazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, and
4H-benzo[1,4]oxazin-3-on-yl; R.sup.1, R.sup.2 and R.sup.3 are
independently selected from --R, --NO.sub.2, --OR, --Cl, --Br, --I,
--F, --CF.sub.3, --C(.dbd.O)R, --C(.dbd.O)OH, --NH.sub.2, --SH,
--NHR, --NR.sub.2, --SR, --SO.sub.3H, --SO.sub.2R, --SO.sub.2NR,
--S(.dbd.O)R, --CN, --OH, --C(.dbd.O)OR, --C(.dbd.O)NR.sub.2,
--NRC(.dbd.O)R, and --NRC(.dbd.O)--OR, wherein R is, independently,
a hydrogen, C.sub.5-6cycloalkyl, C.sub.3-5heterocyclyl, phenyl,
benzyl, C.sub.1-4alkyl or C.sub.2-4alkenyl, and wherein said R is
further optionally substituted with one or more groups selected
from methyl, cyano, methoxy, hydroxy and halogen; Q is selected
from: ##STR137## ##STR138## or Q may be a trivalent group such as
##STR139## which is fused with Ar.sup.1, wherein Ar.sup.1 is a
divalent aromatic group such as 1,2-phenylene.
3. A compound according to claim 1, wherein Ar.sup.1 is selected
from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl; 1-naphthyl,
2-naphthyl, 1,2,3,4-tetrahydro-naphth-1-yl;
1,2,3,4-tetrahydro-naphth-5-yl; 2-thienyl, 3-thienyl, 2-furyl,
2-thiazolyl, benzo[1,3]dioxol-5-yl,
4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl;
2,3-dihydro-benzo[1,4]dioxin-6-yl;
2,3-dihydro-benzo[1,4]dioxin-2-yl; quinol-2-yl, isoquinol-5-yl;
1H-indol-4-yl, 1H-indol-3-yl, 1H-indol-2-yl, 1H-indol-7-yl,
1-pyrroyl, 1H-benzotriazol-5-yl, 1H-benzoimidazol-5-yl,
2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-isoindol-1-on-2-yl;
benzo[1,2,3]thiadiazol-5-yl, benzo[1,2,3]thiadiazol-6-yl,
benzothiazol-6-yl, benzothiazol-2-yl, imidazo[1,2-a]pyridin-2-yl,
2-pyrazinyl, and 4H-benzo[1,4]oxazin-3-on-7-yl, wherein Ar.sup.1 is
further optionally substituted with one or more groups selected
from C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.1-4alkoxy,
C.sub.1-4alkenyloxy, phenoxy, 4-methoxyphenoxy, benzyl, acetoamino,
methylsulfonyl, methoxycarbonyl, nitro, chloro, fluoro, bromo,
iodo, 1-pyrroyl, 2-methyl-pyrro-1-yl, amino, phenylsulfonyl, aceto,
1-piperidinyl, [1,2,3]thiadiazol-4-yl, 4-morpholinyl, methoxy,
ethoxy, isopropyloxy, methythio, cyano, dimethylamino, hydroxy,
methylaminosulfonyl, trifluoromethyl, trifluoromethoxy, phenyl,
4-cyano-benzyl, 4-hydroxyl-phenyl, diethylamino, aminosulfonyl,
cyclohexyl, 1-pyrrolyl, 1H-pyrazol-3-yl, 5-tetrazolyl,
1-piperidinyl, 1-pyrazolyl, methylsulfonylmethyl,
3,5-dimethyl-pyrazolyl, pyrrolidin-2-on-1-yl; and Q is selected
from ##STR140## ##STR141##
4. A compound selected from: ##STR142## ##STR143## ##STR144##
##STR145## ##STR146## ##STR147## ##STR148## ##STR149## ##STR150##
##STR151## ##STR152## ##STR153## ##STR154## ##STR155## ##STR156##
##STR157## ##STR158##
5-6. (canceled)
7. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier.
8. A method for the therapy of depression in a warm-blooded animal,
comprising the step of administering to said animal in need of such
therapy a therapeutically effective amount of a compound according
to claim 1.
9. A process for preparing a compound of formula I, comprising:
##STR159## reacting Ar.sup.1-Q-H with 4-amino-1-methyl piperidine
and a haloformate, wherein Ar.sup.1 is selected from C.sub.6-10aryl
and C.sub.2-9heteroaryl, wherein said C.sub.6-10aryl and
C.sub.2-9heteroaryl are optionally substituted with one or more
groups selected from --R, --NO.sub.2, --OR, --Cl, --Br, --I, --F,
--CF.sub.3, --OCF.sub.3, --C(.dbd.O)R, --C(.dbd.O)OH, --NH.sub.2,
--SH, --NHR, --NR.sub.2, --SR, --SO.sub.3H, --SO.sub.2R,
--SO.sub.2NR, --S(.dbd.O)R, --CN, --OH, --C(.dbd.O)OR,
--C(.dbd.O)NR.sub.2, --NRC(.dbd.O)R, and --NRC(.dbd.O)--OR, wherein
R is, independently, a hydrogen, C.sub.3-6cycloalkyl,
C.sub.3-6heterocyclyl, phenyl, benzyl, C.sub.1-6alkyl or
C.sub.2-6alkenyl and wherein said R is further optionally
substituted with one or more groups selected from methyl, methoxy,
hydroxy and halogen; and Q is a divalent or trivalent group that
connects the carbonyl with Ar.sup.1, wherein said divalent or
trivalent group contains at least one nitrogen, wherein said
nitrogen of Q is connected to the H in Ar.sup.1-Q-H to form an
amino, and said trivalent group is fused with Ar.sup.1; and said
Q-H of Ar.sup.1-Q-H forms an amino group.
10. A process of preparing a compound of formula I comprising:
##STR160## combining Ar.sup.1-Q-H with 4-amino-1-methyl piperidine
and a haloformate, wherein Ar.sup.1 is selected from phenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl; 1-naphthyl, 2-naphthyl,
1,2,3,4-tetrahydro-naphth-1-yl; 1,2,3,4-tetrahydro-naphth-5-yl;
2-thienyl, 3-thienyl, 2-furyl, 2-thiazolyl, benzo[1,3]dioxol-5-yl,
4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl;
2,3-dihydro-benzo[1,4]dioxin-6-yl;
2,3-dihydro-benzo[1,4]dioxin-2-yl; quinol-2-yl, isoquinol-5-yl;
1H-indol-4-yl, 1H-indol-3-yl, 1H-indol-2-yl, 1H-indol-7-yl,
1-pyrroyl, 1H-benzotriazol-5-yl, 1H-benzoimidazol-5-yl,
2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-isoindol-1-on-2-yl;
benzo[1,2,3]thiadiazol-5-yl, benzo[1,2,3]thiadiazol-6-yl,
benzothiazol-6-yl, benzothiazol-2-yl, imidazo[1,2-a]pyridin-2-yl,
2-pyrazinyl, and 4H-benzo[1,4]oxazin-3-on-7-yl, wherein Ar.sup.1 is
further optionally substituted with one or more groups selected
from C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.1-4alkoxy,
C.sub.1-4alkenyloxy, phenoxy, 4-methoxyphenoxy, benzyl, acetoamino,
methylsulfonyl, methoxycarbonyl, nitro, chloro, fluoro, bromo,
iodo, 1-pyrroyl, 2-methyl-pyrro-1-yl, amino, phenylsulfonyl, aceto,
1-piperidinyl, [1,2,3]thiadiazol-4-yl, 4-morpholinyl, methoxy,
ethoxy, isopropyloxy, methythio, cyano, dimethylamino, hydroxy,
methylaminosulfonyl, trifluoromethyl, trifluoromethoxy, phenyl,
4-cyano-benzyl, 4-hydroxyl-phenyl, diethylamino, aminosulfonyl,
cyclohexyl, 1-pyrrolyl, 1H-pyrazol-3-yl, 5-tetrazolyl,
1-piperidinyl, 1-pyrazolyl, methylsulfonylmethyl,
3,5-dimethyl-pyrazolyl, pyrrolidin-2-on-1-yl; and Q is selected
from ##STR161## ##STR162## and wherein the left side nitrogen atom
in the above-identified structures of Q is connected to the H in
Ar.sup.1-Q-H to form an amino group.
Description
FIELD OF THE INVENTION
[0001] This invention relates histamine receptor ligands. More
specifically, the invention relates to histamine H3 receptor
ligands, preparation thereof and uses thereof.
BACKGROUND OF THE INVENTION
[0002] The histamine H3 receptor is of current interest for the
development of new medicaments. This receptor is a presynaptic
autoreceptor located both in the central and the peripheral nervous
system, the skin and in organs such as the lung, the intestine,
probably the spleen and the gastrointestinal tract. Recent evidence
suggests that the H3 receptor shows intrinsic, constitutive
activity, in vitro as well as in vivo (i.e., it is active in the
absence of an agonist. Compounds acting as inverse agonists can
inhibit this activity. The histamine H3 receptor has been
demonstrated to regulate the release of histamine and also of other
neurotransmitters such as serotonin and acetylcholine. Some
histamine H3 ligands such as histamine H3 receptor antagonists or
inverse agonists may increase the release of these
neurotransmitters in the brain whereas other histamine H3 ligands
such as histamine H3 receptor agonists may lead to an inhibition of
the biosynthesis of histamine and an inhibition of the release of
histamine and also of other neurotransmitters. This suggests that
histamine H3 receptor agonists, inverse agonists and antagonists
could be mediators of neuronal activity. Accordingly, the histamine
H3 receptor may be a target for new therapeutics.
[0003] There are publications that disclose the preparation and use
of imidazole derivative histamine H3 ligands. However, there are
needs for additional histamine H3 ligands.
DESCRIPTION OF THE INVENTION
[0004] Unless specified otherwise within this specification, the
nomenclature used in this specification generally follows the
examples and rules stated in Nomenclature of Organic Chemistry,
Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979,
which is incorporated by references herein for its exemplary
chemical structure names and rules on naming chemical
structures.
[0005] The term "C.sub.m-n" or "C.sub.m-n group" used alone or as a
prefix, refers to any group having m to n carbon atoms.
[0006] The term "hydrocarbon" used alone or as a suffix or prefix,
refers to any structure comprising only carbon and hydrogen atoms
up to 14 carbon atoms.
[0007] The term "hydrocarbon radical" or "hydrocarbyl" used alone
or as a suffix or prefix, refers to any structure as a result of
removing one or more hydrogens from a hydrocarbon.
[0008] The term "alkyl" used alone or as a suffix or prefix, refers
to monovalent straight or branched chain hydrocarbon radicals
comprising 1 to about 12 carbon atoms.
[0009] The term "alkylene" used alone or as suffix or prefix,
refers to divalent straight or branched chain hydrocarbon radicals
comprising 1 to about 12 carbon atoms, which serves to links two
structures together.
[0010] The term "alkenyl" used alone or as suffix or prefix, refers
to a monovalent straight or branched chain hydrocarbon radical
having at least one carbon-carbon double bond and comprising at
least 2 up to about 12 carbon atoms.
[0011] The term "alkynyl" used alone or as suffix or prefix, refers
to a monovalent straight or branched chain hydrocarbon radical
having at least one carbon-carbon triple bond and comprising at
least 2 up to about 12 carbon atoms.
[0012] The term "cycloalkyl," used alone or as suffix or prefix,
refers to a monovalent ring-containing hydrocarbon radical
comprising at least 3 up to about 12 carbon atoms.
[0013] The term "cycloalkenyl" used alone or as suffix or prefix,
refers to a monovalent ring-containing hydrocarbon radical having
at least one carbon-carbon double bond and comprising at least 3 up
to about 12 carbon atoms.
[0014] The term "cycloalkynyl" used alone or as suffix or prefix,
refers to a monovalent ring-containing hydrocarbon radical having
at least one carbon-carbon triple bond and comprising about 7 up to
about 12 carbon atoms.
[0015] The term "aryl" used alone or as suffix or prefix, refers to
a monovalent hydrocarbon radical having one or more polyunsaturated
carbon rings having aromatic character, (e.g., 4n+2 delocalized
electrons) and comprising 5 up to about 14 carbon atoms.
[0016] The term "arylene" used alone or as suffix or prefix, refers
to a divalent hydrocarbon radical having one or more
polyunsaturated carbon rings having aromatic character, (e.g., 4n+2
delocalized electrons) and comprising 5 up to about 14 carbon
atoms, which serves to link two structures together.
[0017] The term "heterocycle" used alone or as a suffix or prefix,
refers to a ring-containing structure or molecule having one or
more multivalent heteroatoms, independently selected from N, O, P
and S, as a part of the ring structure and including at least 3 and
up to about 20 atoms in the ring(s). Heterocycle may be saturated
or unsaturated, containing one or more double bonds, and
heterocycle may contain more than one ring. When a heterocycle
contains more than one ring, the rings may be fused or unfused.
Fused rings generally refer to at least two rings share two atoms
therebetween. Heterocycle may have aromatic character or may not
have aromatic character.
[0018] The term "heteroaromatic" used alone or as a suffix or
prefix, refers to a ring-containing structure or molecule having
one or more multivalent heteroatoms, independently selected from N,
O, P and S, as a part of the ring structure and including at least
3 and up to about 20 atoms in the ring(s), wherein the
ring-containing structure or molecule has an aromatic character
(e.g., 4n+2 delocalized electrons).
[0019] The term "heterocyclic group," "heterocyclic moiety,"
"heterocyclic," or "heterocyclo" used alone or as a suffix or
prefix, refers to a radical derived from a heterocycle by removing
one or more hydrogens therefrom.
[0020] The term "heterocyclyl" used alone or as a suffix or prefix,
refers a monovalent radical derived from a heterocycle by removing
one hydrogen therefrom.
[0021] The term "heterocyclylene" used alone or as a suffix or
prefix, refers to a divalent radical derived from a heterocycle by
removing two hydrogens therefrom, which serves to links two
structures together.
[0022] The term "heteroaryl" used alone or as a suffix or prefix,
refers to a heterocyclyl having aromatic character.
[0023] The term "heterocylcoalkyl" used alone or as a suffix or
prefix, refers to a heterocyclyl that does not have aromatic
character.
[0024] The term "heteroarylene" used alone or as a suffix or
prefix, refers to a heterocyclylene having aromatic character.
[0025] The term "heterocycloalkylene" used alone or as a suffix or
prefix, refers to a heterocyclylene that does not have aromatic
character.
[0026] The term "six-membered" used as prefix refers to a group
having a ring that contains six ring atoms.
[0027] The term "five-membered" used as prefix refers to a group
having a ring that contains five ring atoms.
[0028] A five-membered ring heteroaryl is a heteroaryl with a ring
having five ring atoms wherein 1, 2 or 3 ring atoms are
independently selected from N, O and S.
[0029] Exemplary five-membered ring heteroaryls are thienyl, furyl,
pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and
1,3,4-oxadiazolyl.
[0030] A six-membered ring heteroaryl is a heteroaryl with a ring
having six ring atoms wherein 1, 2 or 3 ring atoms are
independently selected from N, O and S.
[0031] Exemplary six-membered ring heteroaryls are pyridyl,
pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
[0032] The term "substituted" used as a prefix refers to a
structure, molecule or group, wherein one or more hydrogens are
replaced with one or more C.sub.1-6hydrocarbon groups, or one or
more chemical groups containing one or more heteroatoms selected
from N, O, S, F, Cl, Br, I, and P. Exemplary chemical groups
containing one or more heteroatoms include --NO.sub.2, --OR, --Cl,
--Br, --I, --F, --CF.sub.3, --C(.dbd.O)R, --C(.dbd.O)OH,
--NH.sub.2, --SH, --NHR, --NR.sub.2, --SR, --SO.sub.3H,
--SO.sub.2R, --S(.dbd.O)R, --CN, --OH, --C(.dbd.O)OR,
--C(.dbd.O)NR.sub.2, --NRC(.dbd.O)R, oxo (.dbd.O), imino (.dbd.NR),
thio (.dbd.S), and oximino (.dbd.N--OR), wherein each "R" is a
C.sub.1-6hydrocarbyl. For example, substituted phenyl may refer to
nitrophenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc.,
wherein the nitro, methoxy, chloro, and amino groups may replace
any suitable hydrogen on the phenyl ring.
[0033] The term "substituted" used as a suffix of a first
structure, molecule or group, followed by one or more names of
chemical groups refers to a second structure, molecule or group,
which is a result of replacing one or more hydrogens of the first
structure, molecule or group with the one or more named chemical
groups. For example, a "phenyl substituted by nitro" refers to
nitrophenyl.
[0034] Heterocycle includes, for example, monocyclic heterocycles
such as: aziridine, oxirane, thiirane, azetidine, oxetane,
thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine,
pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran
tetrahydrofuran, thiophane, piperidine,
1,2,3,6-tetrahydro-pyridine, piperazine, morpholine,
thiomorpholine, pyran, thiopyran, 2,3-dihydropyran,
tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane,
dioxane, homopiperidine, 2,3,4,7-tetrahydro-1H-azepine
homopiperazine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and
hexamethylene oxide.
[0035] In addition, heterocycle includes aromatic heterocycles, for
example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene,
furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole,
isothiazole, isoxazole, 1,2,3-triazole, tetrazole,
1,2,3-thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole,
1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole,
1,3,4-thiadiazole, and 1,3,4-oxadiazole.
[0036] Additionally, heterocycle encompass polycyclic heterocycles,
for example, indole, indoline, isoindoline, quinoline,
tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline,
1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran,
2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman,
isochroman, xanthene, phenoxathiin, thianthrene, indolizine,
isoindole, indazole, purine, phthalazine, naphthyridine,
quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine,
perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine,
1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole,
benzimidazole, benztriazole, thioxanthine, carbazole, carboline,
acridine, pyrolizidine, and quinolizidine.
[0037] In addition to the polycyclic heterocycles described above,
heterocycle includes polycyclic heterocycles wherein the ring
fusion between two or more rings includes more than one bond common
to both rings and more than two atoms common to both rings.
Examples of such bridged heterocycles include quinuclidine,
diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
[0038] Heterocyclyl includes, for example, monocyclic
heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl,
azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl,
2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl,
thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl,
morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl,
2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl,
1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl,
2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl,
4,7-dihydro-1,3-dioxepinyl, and hexamethylene oxidyl.
[0039] In addition, heterocyclyl includes aromatic heterocyclyls or
heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl,
thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,
1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
[0040] Additionally, heterocyclyl encompasses polycyclic
heterocyclyls (including both aromatic or non-aromatic), for
example, indolyl, indolinyl, isoindolinyl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl,
2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl,
isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl,
isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,
phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl,
benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl,
thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl,
and quinolizidinyl.
[0041] In addition to the polycyclic heterocyclyls described above,
heterocyclyl includes polycyclic heterocyclyls wherein the ring
fusion between two or more rings includes more than one bond common
to both rings and more than two atoms common to both rings.
Examples of such bridged heterocycles include quinuclidinyl,
diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
[0042] The term "alkoxy" used alone or as a suffix or prefix,
refers to radicals of the general formula --O--R, wherein R is
selected from a hydrocarbon radical. Exemplary alkoxy includes
methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy,
cyclopropylmethoxy, allyloxy, and propargyloxy.
[0043] The term "amine" or "amino" used alone or as a suffix or
prefix, refers to radicals of the general formula --NRR', wherein R
and R' are independently selected from hydrogen or a hydrocarbon
radical.
[0044] Halogen includes fluorine, chlorine, bromine and iodine.
[0045] "Halogenated," used as a prefix of a group, means one or
more hydrogens on the group is replaced with one or more
halogens.
[0046] "RT" or "rt" means room temperature.
[0047] In one aspect, the invention provides a compound of formula
I, a pharmaceutically acceptable salt thereof, diastereomers
thereof, enantiomers thereof, and mixtures thereof: ##STR2##
wherein
[0048] Ar.sup.1 is selected from C.sub.6-10aryl and
C.sub.2-9heteroaryl, wherein said C.sub.6-10aryl and
C.sub.2-9heteroaryl are optionally substituted with one or more
groups selected from --R, --NO.sub.2, --OR, --Cl, --Br, --I, --F,
--CF.sub.3, --OCF.sub.3, --C(.dbd.O)R, --C(.dbd.O)OH, --NH.sub.2,
--SH, --NHR, --NR.sub.2, --SR, --SO.sub.3H, --SO.sub.2R,
--SO.sub.2NR, --S(.dbd.O)R, --CN, --OH, --C(.dbd.O)OR,
--C(.dbd.O)NR.sub.2, --NRC(.dbd.O)R, and --NRC(.dbd.O)--OR, wherein
R is, independently, a hydrogen, C.sub.3-6cycloalkyl,
C.sub.3-6heterocyclyl, phenyl, benzyl, C.sub.1-6alkyl or
C.sub.2-6alkenyl and wherein said R is further optionally
substituted with one or more groups selected from methyl, methoxy,
hydroxy and halogen; and
[0049] Q is a divalent or trivalent group that connects the
carbonyl with Ar.sup.1, wherein said divalent or trivalent group
contains at least one nitrogen, said nitrogen is directly connected
to the carbonyl group of formula I to form an amide bond
therebetween, and said trivalent group is fused with Ar.sup.1.
[0050] In one embodiment, the compound of the present invention may
be a compound of formula I, wherein Ar.sup.1 is represented by
##STR3##
[0051] wherein Ar is selected from phenyl, pyridyl, naphthyl,
1,2,3,4-tetrahydro-naphthyl; thienyl, furyl, thiazolyl,
benzo[1,3]dioxolyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridinyl;
2,3-dihydro-benzo[1,4]dioxinyl; quinolyl; isoquinolyl; indolyl;
pyrroyl, benzotriazolyl; benzoimidazolyl, 2,3-dihydro-benzofuranyl;
2,3-dihydro-isoindol-1-on-yl; benzo[1,2,3]thiadiazolyl,
benzothiazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, and
4H-benzo[1,4]oxazin-3-on-yl;
[0052] R.sup.1, R.sup.2 and R.sup.3 are independently selected from
--R, --NO.sub.2, --OR, --Cl, --Br, --I, --F, --CF.sub.3,
--C(.dbd.O)R, --C(.dbd.O)OH, --NH.sub.2, --SH, --NHR, --NR.sub.2,
--SR, --SO.sub.3H, --SO.sub.2R, --SO.sub.2NR, --S(.dbd.O)R, --CN,
--OH, --C(.dbd.O)OR, --C(.dbd.O)NR.sub.2, --NRC(--O)R, and
--NRC(.dbd.O)--OR, wherein R is, independently, a hydrogen,
C.sub.5-6cycloalkyl, C.sub.3-5heterocyclyl, phenyl, benzyl,
C.sub.1-4alkyl or C.sub.2-4alkenyl, and wherein said R is further
optionally substituted with one or more groups selected from
methyl, cyano, methoxy, hydroxy and halogen;
[0053] Q is selected from: ##STR4## ##STR5## or Q may be a
trivalent group such as ##STR6## which is fused with Ar.sup.1,
wherein Ar.sup.1 is a divalent aromatic group such as
1,2-phenylene.
[0054] In another embodiment, the compounds of the present
invention are represented by formula I, wherein Ar.sup.1 is
selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl; 1-naphthyl,
2-naphthyl, 1,2,3,4-tetrahydro-naphth-1-yl;
1,2,3,4-tetrahydro-naphth-5-yl; 2-thienyl, 3-thienyl, 2-furyl,
2-thiazolyl, benzo[1,3]dioxol-5-yl,
4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl;
2,3-dihydro-benzo[1,4]dioxin-6-yl;
2,3-dihydro-benzo[1,4]dioxin-2-yl; quinol-2-yl, isoquinol-5-yl;
1H-indol-4-yl, 1H-indol-3-yl, 1H-indol-2-yl, 1H-indol-7-yl,
1-pyrroyl, 1H-benzotriazol-5-yl, 1H-b enzoimidazol-5-yl,
2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-isoindol-1-on-2-yl;
benzo[1,2,3]thiadiazol-5-yl, benzo[1,2,3]thiadiazol-6-yl,
benzothiazol-6-yl, benzothiazol-2-yl, imidazo[1,2-a]pyridin-2-yl,
2-pyrazinyl, and 4H-benzo[1,4]oxazin-3-on-7-yl, wherein Ar.sup.1 is
further optionally substituted with one or more groups selected
from C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.1-4alkoxy,
C.sub.1-4alkenyloxy, phenoxy, 4-methoxyphenoxy, benzyl, acetoamino,
methylsulfonyl, methoxycarbonyl, nitro, chloro, fluoro, bromo,
iodo, 1-pyrroyl, 2-methyl-pyrro-1-yl, amino, phenylsulfonyl, aceto,
1-piperidinyl, [1,2,3]thiadiazol-4-yl, 4-morpholinyl, methoxy,
ethoxy, isopropyloxy, methythio, cyano, dimethylamino, hydroxy,
methylaminosulfonyl, trifluoromethyl, trifluoromethoxy, phenyl,
phenoxy, 4-cyano-benzyl, 4-hydroxyl-phenyl, diethylamino,
methylsulfonyl, aminosulfonyl, cyclohexyl, 1-pyrrolyl,
1H-pyrazol-3-yl, 5-tetrazolyl, 1-piperidinyl, 1-pyrazolyl,
methylsulfonylmethyl, 3,5-dimethyl-pyrazolyl, pyrrolidin-2-on-1-yl;
and
[0055] Q is selected from ##STR7## ##STR8##
[0056] In a further embodiment, the compounds of the present
invention are selected from: ##STR9## ##STR10## ##STR11## ##STR12##
##STR13## ##STR14## ##STR15## ##STR16## ##STR17## ##STR18##
##STR19## ##STR20## ##STR21## ##STR22## ##STR23## ##STR24##
##STR25##
[0057] It will be understood that when compounds of the present
invention contain one or more chiral centers, the compounds of the
invention may exist in, and be isolated as, enantiomeric or
diastereomeric forms, or as a racemic mixture. The present
invention includes any possible enantiomers, diastereomers,
racemates or mixtures thereof, of a compound of Formula I. The
optically active forms of the compound of the invention may be
prepared, for example, by chiral chromatographic separation of a
racemate, by synthesis from optically active starting materials or
by asymmetric synthesis based on the procedures described
thereafter.
[0058] It will also be appreciated that certain compounds of the
present invention may exist as geometrical isomers, for example E
and Z isomers of alkenes. The present invention includes any
geometrical isomer of a compound of Formula I. It will further be
understood that the present invention encompasses tautomers of the
compounds of the formula I.
[0059] It will also be understood that certain compounds of the
present invention may exist in solvated, for example hydrated, as
well as unsolvated forms. It will further be understood that the
present invention encompasses all such solvated forms of the
compounds of the formula I.
[0060] Within the scope of the invention are also salts of the
compounds of the formula I. Generally, pharmaceutically acceptable
salts of compounds of the present invention may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound, for example an alkyl amine with a
suitable acid, for example, HCl or acetic acid, to afford a
physiologically acceptable anion. It may also be possible to make a
corresponding alkali metal (such as sodium, potassium, or lithium)
or an alkaline earth metal (such as a calcium) salt by treating a
compound of the present invention having a suitably acidic proton,
such as a carboxylic acid or a phenol with one equivalent of an
alkali metal or alkaline earth metal hydroxide or alkoxide (such as
the ethoxide or methoxide), or a suitably basic organic amine (such
as choline or meglumine) in an aqueous medium, followed by
conventional purification techniques.
[0061] In one embodiment, the compound of formula I above may be
converted to a pharmaceutically acceptable salt or solvate thereof,
particularly, an acid addition salt such as a hydrochloride,
hydrobromide, phosphate, acetate, fumarate, maleate, tartrate,
citrate, methanesulphonate or p-toluenesulphonate.
[0062] The compounds of the present invention are useful in the
treatment of a wide range of conditions and disorders in which an
interaction with the histamine H3 receptor is beneficial. Thus, the
compounds may find use e.g. in the treatment of diseases of the
central nervous system, the peripheral nervous system, the
cardiovascular system, the pulmonary system, the gastrointestinal
system and the endocrinological system.
[0063] The compounds of the present invention are useful in
therapy, especially for the treatment of various depression
conditions.
[0064] Compounds of the invention are useful as immunomodulators,
especially for autoimmune diseases, such as arthritis, for skin
grafts, organ transplants and similar surgical needs, for collagen
diseases, various allergies, for use as anti-tumour agents and anti
viral agents.
[0065] Compounds of the invention are useful for the treatment of
obesity, epilepsy, Alzheimer's disease, dementia, schizophrenia,
cognitive defect, rhinitis, cognition disorders, central nervous
system disease, neurological disorder, epilepsy, attention deficit
hyperactivity disorder, eating disorder, allergic rhinitis,
allergy, inflammation, migraine, sleep disorder, narcolepsy,
anxiety disorder, psychiatric conditions, depression, multiple
sclerosis, anxiety, bipolar disorder, stroke, sleep disorder,
mental disorder, cognitive disorder and non-insulin dependent
diabetes.
[0066] Compounds of the invention are useful as an anti-depression
agent. Combinations of agents with different properties may be used
to achieve a balance of effects needed to treat depression.
[0067] Also within the scope of the invention is the use of any of
the compounds according to the formula I above, for the manufacture
of a medicament for the treatment of any of the conditions
discussed above.
[0068] A further aspect of the invention is a method for the
treatment of a subject suffering from any of the conditions
discussed above, whereby an effective amount of a compound
according to the formula I above, is administered to a patient in
need of such treatment.
[0069] Thus, the invention provides a compound of formula I, or
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined for use in therapy.
[0070] In a further aspect, the present invention provides the use
of a compound of formula I, or a pharmaceutically acceptable salt
or solvate thereof, as hereinbefore defined in the manufacture of a
medicament for use in therapy.
[0071] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The term "therapeutic" and
"therapeutically" should be contrued accordingly. The term
"therapy" within the context of the present invention further
encompasses to administer an effective amount of a compound of the
present invention, to mitigate either a pre-existing disease state,
acute or chronic, or a recurring condition. This definition also
encompasses prophylactic therapies for prevention of recurring
conditions and continued therapy for chronic disorders.
[0072] In use for therapy in a warm-blooded animal such as a human,
the compound of the invention may be administered in the form of a
conventional pharmaceutical composition by any route including
orally, intramuscularly, subcutaneously, topically, intranasally,
intraperitoneally, intrathoracially, intravenously, epidurally,
intrathecally, intracerebroventricularly and by injection into the
joints.
[0073] In one embodiment of the invention, the route of
administration may be orally, intravenously or intramuscularly.
[0074] The dosage will depend on the route of administration, the
severity of the disease, age and weight of the patient and other
factors normally considered by the attending physician, when
determining the individual regimen and dosage level at the most
appropriate for a particular patient.
[0075] For preparing pharmaceutical compositions from the compounds
of this invention, inert, pharmaceutically acceptable carriers can
be either solid and liquid. Solid form preparations include
powders, tablets, dispersible granules, capsules, cachets, and
suppositories.
[0076] A solid carrier can be one or more substances, which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or table disintegrating agents; it can
also be an encapsulating material.
[0077] In powders, the carrier is a finely divided solid, which is
in a mixture with the finely divided compound of the invention, or
the active component. In tablets, the active component is mixed
with the carrier having the necessary binding properties in
suitable proportions and compacted in the shape and size
desired.
[0078] For preparing suppository compositions, a low-melting wax
such as a mixture of fatty acid glycerides and cocoa butter is
first melted and the active ingredient is dispersed therein by, for
example, stirring. The molten homogeneous mixture in then poured
into convenient sized moulds and allowed to cool and solidify.
[0079] Suitable carriers are magnesium carbonate, magnesium
stearate, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
[0080] The term composition is also intended to include the
formulation of the active component with encapsulating material as
a carrier providing a capsule in which the active component (with
or without other carriers) is surrounded by a carrier which is thus
in association with it. Similarly, cachets are included.
[0081] Tablets, powders, cachets, and capsules can be used as solid
dosage forms suitable for oral administration.
[0082] Liquid form compositions include solutions, suspensions, and
emulsions. For example, sterile water or water propylene glycol
solutions of the active compounds may be liquid preparations
suitable for parenteral administration. Liquid compositions can
also be formulated in solution in aqueous polyethylene glycol
solution.
[0083] Aqueous solutions for oral administration can be prepared by
dissolving the active component in water and adding suitable
colorants, flavoring agents, stabilizers, and thickening agents as
desired. Aqueous suspensions for oral use can be made by dispersing
the finely divided active component in water together with a
viscous material such as natural synthetic gums, resins, methyl
cellulose, sodium carboxymethyl cellulose, and other suspending
agents known to the pharmaceutical formulation art.
[0084] Depending on the mode of administration, the pharmaceutical
composition will preferably include from 0.05% to 99% w (percent by
weight), more preferably from 0.10 to 50% w, of the compound of the
invention, all percentages by weight being based on total
composition.
[0085] A therapeutically effective amount for the practice of the
present invention may be determined, by the use of known criteria
including the age, weight and response of the individual patient,
and interpreted within the context of the disease which is being
treated or which is being prevented, by one of ordinary skills in
the art.
[0086] Within the scope of the invention is the use of any compound
of formula I as defined above for the manufacture of a
medicament.
[0087] Also within the scope of the invention is the use of any
compound of formula I for the manufacture of a medicament for the
therapy of depression.
[0088] Additionally provided is the use of any compound according
to Formula I for the manufacture of a medicament for the therapy of
various depression conditions.
[0089] A further aspect of the invention is a method for therapy of
a subject suffering from any of the conditions discussed above,
whereby an effective amount of a compound according to the formula
I above, is administered to a patient in need of such therapy.
[0090] Additionally, there is provided a pharmaceutical composition
comprising a compound of Formula I, or a pharmaceutically
acceptable salt thereof, in association with a pharmaceutically
acceptable carrier.
[0091] Particularly, there is provided a pharmaceutical composition
comprising a compound of Formula I, or a pharmaceutically
acceptable salt thereof, in association with a pharmaceutically
acceptable carrier for therapy, more particularly for therapy of
depression.
[0092] Further, there is provided a pharmaceutical composition
comprising a compound of Formula I, or a pharmaceutically
acceptable salt thereof, in association with a pharmaceutically
acceptable carrier use in any of the conditions discussed
above.
[0093] In a further aspect, the invention provides a process for
preparing a compound of formula I, comprising: ##STR26##
[0094] reacting Ar.sup.1-Q-H with 4-amino-1-methyl piperidine and a
haloformate, wherein
[0095] Ar.sup.1 is selected from C.sub.6-10 aryl and
C.sub.2-9heteroaryl, wherein said C.sub.6-10aryl and
C.sub.2-9heteroaryl are optionally substituted with one or more
groups selected from --R, --NO.sub.2, --OR, --Cl, --Br, --I, --F,
--CF.sub.3, --OCF.sub.3, --C(.dbd.O)R, --C(.dbd.O)OH, --NH.sub.2,
--SH, --NHR, --NR.sub.2, --SR, --SO.sub.3H, --SO.sub.2R,
--SO.sub.2NR, --S(.dbd.O)R, --CN, --OH, --C(.dbd.O)OR,
--C(.dbd.O)NR.sub.2, --NRC(.dbd.O)R, and --NRC(.dbd.O)--OR, wherein
R is, independently, a hydrogen, C.sub.3-6cycloalkyl,
C.sub.3-6heterocyclyl, phenyl, benzyl, C.sub.1-6alkyl or
C.sub.2-6alkenyl and wherein said R is further optionally
substituted with one or more groups selected from methyl, methoxy,
hydroxy and halogen; and
[0096] Q is a divalent or trivalent group that connects the
carbonyl with Ar.sup.1, wherein said divalent or trivalent group
contains at least one nitrogen, wherein said nitrogen of Q is
connected to the H in Ar.sup.1-Q-H to form an amino, and said
trivalent group is fused with Ar.sup.1; and said Q-H of
Ar.sup.1-Q-H forms an amino group.
[0097] In one embodiment, the process of preparing a compound of
formula I comprising: ##STR27##
[0098] combining Ar.sup.1-Q-H with 4-amino-1-methyl piperidine and
a haloformate,
[0099] wherein Ar.sup.1 is selected from phenyl, 2-pyridyl,
3-pyridyl, 4-pyridyl; 1-naphthyl, 2-naphthyl,
1,2,3,4-tetrahydro-naphth-1-yl; 1,2,3,4-tetrahydro-naphth-5-yl;
2-thienyl, 3-thienyl, 2-furyl, 2-thiazolyl, benzo[1,3]dioxol-5-yl,
4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl;
2,3-dihydro-benzo[1,4]dioxin-6-yl;
2,3-dihydro-benzo[1,4]dioxin-2-yl; quinol-2-yl, isoquinol-5-yl;
1H-indol-4-yl, 1H-indol-3-yl, 1H-indol-2-yl, 1H-indol-7-yl,
1-pyrroyl, 1H-benzotriazol-5-yl, 1H-benzoimidazol-5-yl,
2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-isoindol-1-on-2-yl;
benzo[1,2,3]thiadiazol-5-yl, benzo[1,2,3]thiadiazol-6-yl,
benzothiazol-6-yl, benzothiazol-2-yl, imidazo[1,2-a]pyridin-2-yl,
2-pyrazinyl, and 4H-benzo[1,4]oxazin-3-on-7-yl, wherein Ar.sup.1 is
further optionally substituted with one or more groups selected
from C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.1-4alkoxy,
C.sub.1-4alkenyloxy, phenoxy, 4-methoxyphenoxy, benzyl, acetoamino,
methylsulfonyl, methoxycarbonyl, nitro, chloro, fluoro, bromo,
iodo, 1-pyrroyl, 2-methyl-pyrro-1-yl, amino, phenylsulfonyl, aceto,
1-piperidinyl, [1,2,3]thiadiazol-4-yl, 4-morpholinyl, methoxy,
ethoxy, isopropyloxy, methythio, cyano, dimethylamino, hydroxy,
methylaminosulfonyl, trifluoromethyl, trifluoromethoxy, phenyl,
phenoxy, 4-cyano-benzyl, 4-hydroxyl-phenyl, diethylamino,
methylsulfonyl, aminosulfonyl, cyclohexyl, 1-pyrrolyl,
1H-pyrazol-3-yl, 5-tetrazolyl, 1-piperidinyl, 1-pyrazolyl,
methylsulfonylmethyl, 3,5-dimethyl-pyrazolyl, pyrrolidin-2-on-1-yl;
and
[0100] Q is selected from ##STR28## ##STR29## and wherein the left
side nitrogen atom in the above-identified structures of Q is
connected to the H in Ar.sup.1-Q-H to form an amino group.
[0101] In a particular embodiment, the step of combining
Ar.sup.1-Q-H with 4-amino-1-methyl piperidine and a haloformate may
be carried out at ambient temperature and in the presence of
organic base such as diisopropyletihylamine. The haloformate may be
4-nitrophenyl chloroformate.
Biological Evaluation
[0102] The compounds of the invention are found to be active
towards H3 receptors in warm-blooded animal, e.g., human.
Particularly the compounds of the invention are found to be
effective H3 receptor ligands. In vitro assays, infra, demonstrate
these surprising activities. These activities may be related to in
vivo activity and may not be linearly correlated with binding
affinity. In these in vitro assays, a compound is tested for their
activity toward H3 receptors and pIC.sub.50 is obtained to
determine the activity for a particular compound towards H3
receptors.
FLIPR Assay Identification of Antagonists of the Human H3
Receptor
Cell Culture:
[0103] H3 receptor activation in response to histamine mediates
intracellular Ca.sup.2+ mobilization in human H3 receptor
transfected CHO--K.sup.1 cells. This increase in Ca.sup.2+ can be
measured using the fluorometric imaging plate reader (FLIPR)
employing Fluo-3AM loaded H3 receptor transfected cells.
CHO--H3-G.alpha.16 transfected cells were cultured in T225 cm.sup.2
tissue culture flasks as monolayers in NUT Hams (with 1% (v/v)
Glutamine) supplemented with 10% (v/v) heat inactivated fetal
bovine serum and grown under 1 mg/ml. Geneticin antibiotic
selection and 1 mg/ml Zeocin selection. Cultures were maintained at
37.degree. C. in a humidified atmosphere of 5% CO.sub.2 and
passaged every 3 days.
Assay Buffer:
[0104] To 1000 mL of Hanks Balanced Salt solution, add 4.8 g of
HEPES and 0.714 g probenecid (which is dissolved in 5 mL 1 M NaOH
and added to the solution). This buffer is pH adjusted to 7.4 with
NaOH. Assay Buffer contains 10% DMSO (v/v) was prepared for the
compound preparation plates. Usually 200 ml (containing 20 ml neat
DMSO) will be sufficient for 12.times.384 plates.
Loading Buffer:
[0105] To 120 mL Assay Buffer 100 mg BSA and 1 vial MDC FLIPR
Calcium assay reagent (dissolved in assay buffer) was added
immediately prior to loading cells:
Compound Vehicle Control Buffer:
[0106] 400 .mu.L DMSO was added to 20 mL Assay Buffer to produce 2%
(v/v) solution (0.4% (v/v) final)
FLIPR Assay
[0107] Histamine EC50 determination: Cells were harvested using
1.times. dissociation solution and plated onto poly-D-lysine coated
FLIPR plates at 1.0.times.10.sup.4 cells per well 18-24 hours prior
to experiment. Media was removed from the cells by tipping and the
plates gently blotted onto tissue to remove any excess medium. 30
.mu.L loading buffer was added to all wells for 90 min at
37.degree. C.
[0108] 96 well histamine EC50 plate was made and then 40 .mu.L was
indexed into 4 quadrants in a 384 well plate. 96 well compound
vehicle plates were made and indexed into a quadrant of a 384 well
plate. Plates were transferred to FLIPR and run using a standard
protocol. The results were used to calculate an EC50 for
histamine.
[0109] Compound testing: Cells were harvested using 1.times.
dissociation solution and plated onto poly-D-lysine coated FLIPR
plates at 1.0.times.10.sup.4 cells per well 18-24 hours prior to
experiment. Media was removed from the cells by tipping and the
plates gently blotted onto tissue to remove any excess medium. 30
.mu.L loading buffer was added to all wells for 90 min at
37.degree. C. 96 well histamine plate (.times.10 EC50) was made and
then 60 .mu.L was indexed into 4 quadrants in a 384 well plate.
Each 96 well compound plate was made and indexed into a quadrant of
a 384 well plate. An ATP plate was made in a 96 well plate and then
60 .mu.L was indexed into 4 quadrants in a 384 well plate. Plates
transferred to FLIPR and run using a standard protocol. 30 .mu.L of
cells in loading buffer were placed in the wells of FLIPR 384
plate, 10 .mu.L compound solution was added, values were read for 5
min to determine compound effects, 10 .mu.L agonist solution was
added, values were read to determine agonist response, 10 .mu.L ATP
added to and values were read for 5 min to determine ATP
response.
[0110] Final assay concentrations: Compound concentration range=10
.mu.M to 0.1 .mu.M; Vehicle 0.4% DMSO; histamine=2.times.
calculated EC50; ATP=11 .mu.M
Assay for Inhibitors of [.sup.3H]-Histamine Binding to Human
Recombinant H4 Receptor.
[0111] pIC.sub.50 values were determined for compounds of the
invention with a binding assay that allows the identification of
inhibitors of [.sup.3H]-histamine by binding to membranes from CHO
cells that over-express human recombinant H4 receptors. Cells
suitable for performing this assay are commercially available, for
example from Euroscreen as catalogue number 1220;
[.sup.3H]-histamine suitable for performing this assay is
commercially available, for example from Amersham as catalogue
number TRK 631.
[0112] Compounds were dissolved in 500 .mu.l of DMSO and diluted in
DMSO to yield a 1 mM stock based on the formula weight of the
compound. Stock solutions were diluted serially in DMSO in half log
steps to give compound concentrations of 1000, 300, 100, 30 and 10
.mu.M. Typically 5 point duplicate curves were determined. For 10
point curves single concentrations were typically 1000, 300, 100,
30, 10, 3, 1, 0.3, 0.1 and 0.03 .mu.M. Assay buffer was added to
each of the above concentrations to give 10% (v/v) DMSO (1:10
dilution). 5 of each diluted compound solution assayed in duplicate
at a final compound concentration range of 10, 3, 1, 0.3 and 0.1
.mu.M in 1% (v/v) DMSO. More active compounds were assayed at lower
concentrations. Assays were performed in 96 deep well plates
containing 0.1-10 .mu.M compounds or 20 .mu.M histamine; 0.015 mg
protein/well H4 membranes and 3.9 nM of [.sup.3]H-histamine in a
final volume of 200 .mu.l. Plates were incubated at room
temperature for 1.5 hours. The contents of the wells was captured
on filters, washed 2.times.1 mL with Tris/EDTA wash buffer. The
filters were dried for about 2 hrs at 60.degree. C. and the
[.sup.3H] determined by scintillation counting.
[0113] Data was analyzed to construct inhibition curves and
pIC.sub.50 estimated by non-linear regression using a 4 parameter
logistic model. The IC.sub.50 is the concentration (of compound
giving 50% inhibition relative to the plate controls. Thioperamide
was used as the standard compound in this assay.
[0114] % Inhibition=100-((sample reading-NSB reading)/(control
reading-NSB reading).times.100)
[0115] pIC.sub.50=-log(IC.sub.50)
EXAMPLES
[0116] The invention will further be described in more detail by
the following Examples which describe methods whereby compounds of
the present invention may be prepared, purified, analyzed and
biologically tested, and which are not to be construed as limiting
the invention.
Abbreviation Used in the Following Examples and General Process
Conditions:
[0117] aq.: aqueous;
[0118] atm: atmospheric pressure;
[0119] BOC: 1,1-dimethylethoxycarbonyl;
[0120] ACN: acetonitrile;
[0121] DCM: dichloromethane;
[0122] DMR: N,N-dimethylformamide;
[0123] DMSO: dimethyl sulfoxide;
[0124] EtOH: ethanol;
[0125] Et.sub.2O: diethyl ether;
[0126] EtOAc: ethyl acetate;
[0127] h: hour(s);
[0128] HPLC: high performance liquid chromatography;
[0129] EDC-HCl: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride;
[0130] HOBT: 1-hydroxybenzotriazole;
[0131] MeOH: methanol;
[0132] min: minutes;
[0133] MS: mass spectrum;
[0134] NMR: nuclear magnetic resonance;
[0135] psi: pounds per square inch;
[0136] RT: room temperature;
[0137] sat.: saturated;
[0138] TEA: triethylamine;
[0139] TFA: trifluoroacetic acid;
[0140] THF: tetrahydrofuran.
[0141] Temperatures are given in degrees Celsius (.degree. C.).
Unless otherwise stated, operations were carried out at room or
ambient temperature (18-25.degree. C.).
[0142] Chromatography means flash column chromatography on silica
gel unless otherwise noted. Solvent mixture compositions are given
as volume percentages or volume ratios.
[0143] Where noted that a final compound was converted to the
citrate salt, the free base was dissolved in MeOH, DCM, or ACN,
combined with citric acid (1.0 equivalents) in MeOH, concentrated
under reduced pressure and dried under vacuum (25-60.degree. C.).
When indicated that the salt was isolated by filtration from
Et.sub.2O, the citrate salt of the compound was stirred in
Et.sub.2O for 4-18 h, recovered by filtration, washed with
Et.sub.2O, and dried under vacuum (25-60.degree. C.).
Example 1
1-(3,4-Dichloro-benzyl)-3-(1-methyl-piperidin-4-yl)-urea
[0144] To a solution of 3,4-dichlorobenzylamine (0.195 g, 1.11
mmol) and diisopropylethylamine (0.193 mL, 1.11 mmol) in 4 mL of
THF was added a preformed solution of 4-nitrophenyl chloroformate
(0.223 g, 1.11 mmol) in 4 mL of THF. The reaction mixture was
stirred at RT for 3.5 h. To this solution was added
4-amino-1-methyl piperidine (0.500 g, 4.38 mmol) and the resulting
solution was stirred at RT for 16 h. The reaction mixture was
concentrated under reduced pressure, diluted with EtOAc (50 mL) and
the solution was washed with saturated aqueous sodium bicarbonate
(2.times.50 mL) and brine (50 mL). The solvent was removed under
reduced pressure and the residue was subjected to supercritical
fluid chromatography (21 mm.times.150 mm diol-bonded SiO.sub.2 (6
.mu.m particle size), isocratic method, 25% MeOH (containing 0.5%
isopropyl amine) in CO.sub.2) to afford the title compound as a
white solid (0.0744 g, 22%). MS m/z 316.2 (M+H).sup.+; .sup.1H NMR
(300.1 MHz, DMSO-d.sub.6) .delta. 1.26-1.39 (m, 2H), 1.69-1.74 (m,
2H), 1.94 (t, J=10.9 Hz, 2H), 2.13 (s, 3H), 2.61-2.65 (m, 2H),
3.34-3.38 (m, 1H), 4.18 (d, J=6.1 Hz, 2H), 5.95 (d, J=7.9 Hz, 1H),
6.29 (t, J=6.0 Hz, 1H), 7.22 (dd, J=8.2, 2.0 Hz, 1H), 7.46 (d,
J=1.9 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H).
[0145] The above procedure may be used to synthesize the following
compounds: TABLE-US-00001 Example Exact No. Structure Name MW Mass
MH+ 1. ##STR30## N-(3,4-dichlorobenzyl)-N'-(1-
methylpiperidin-4-yl)urea 316.23 315.1 316.1 2. ##STR31##
3-benzyl-1-methyl-1-(1- methylpiperidin-4-yl)urea 261.37 261.2
262.2 3. ##STR32## 1-methyl-1-(1-methylpiperidin-4-yl)-
3-(2-(thiophen-2-yl)ethyl)urea 281.42 281.2 282.2 4. ##STR33##
N-tert-butyl-4-oxo-1-phenyl-1,3,8- triazaspiro[4.5]decane-8-
carboxamide 330.43 330.2 331.2 5. ##STR34##
1-methyl-1-(1-methylpiperidin-4-yl)- 3-phenethylurea 275.39 275.2
276.2 6. ##STR35## 1-(1-methylpiperidin-4-yl)-3-(4-
morpholinobenzyl)urea 332.45 332.2 333.2 7. ##STR36##
1-(1-methylpiperidin-4-yl)-3-(4- (trifluoromethyl)benzyl)urea
315.34 315.2 316.2 8. ##STR37## 1-(imidazo[1,2-a]pyridin-2-
ylmethyl)-3-(1-methylpiperidin-4- yl)urea 287.37 287.2 288.2 9.
##STR38## 1-(2,5-difluorobenzyl)-3-(1- methylpiperidin-4-yl)urea
283.32 283.1 284.2 10. ##STR39## 1-(2,4-dimethoxybenzyl)-3-(1-
methylpiperidin-4-yl)urea 307.39 307.2 308.2 11. ##STR40##
1-(2,6-dimethylbenzyl)-3-(1- methylpiperidin-4-yl)urea 275.39 275.2
276.2 12. ##STR41## 1-(3-fluoro-4-methylbenzyl)-3-(1-
methylpiperidin-4-yl)urea 279.36 279.2 280.2 13. ##STR42##
1-(2,4-dichloro-6-methylbenzyl)-3- (1-methylpiperidin-4-yl)urea
330.26 329.1 330.1 14. ##STR43## 1-(3,5-dimethylbenzyl)-3-(1-
methylpiperidin-4-yl)urea 275.39 275.2 276.2 15. ##STR44##
1-(2-fluoro-6-(4- methoxyphenoxy)benzyl)-3-(1-
methylpiperidin-4-yl)urea 387.45 387.2 388.2 16. ##STR45##
1-(2-(furan-2-yl)ethyl)-3-(1- methylpiperidin-4-yl)urea 251.33
251.2 252.2 17. ##STR46## 1-(2-(1-(4-cyanobenzyl)-1H-
imidazol-4-yl)ethyl)-3-(1- methylpiperidin-4-yl)urea 366.47 366.2
367.2 18. ##STR47## 1-(1-methylpiperidin-4-yl)-3-(4-
(methylthio)benzyl)urea 293.43 293.2 294.2 19. ##STR48##
1-(1-methylpiperidin-4-yl)-3-(4- phenoxybenzyl)urea 339.44 339.2
340.2 20. ##STR49## 1-(4-fluorobenzyl)-3-(1-
methylpiperidin-4-yl)urea 265.33 265.2 266.2 21. ##STR50##
1-(2-chlorophenethyl)-3-(1- methylpiperidin-4-yl)urea 295.81 295.1
296.2 22. ##STR51## 1-(3-bromo-4-methoxyphenethyl)-3-
(1-methylpiperidin-4-yl)urea 370.29 369.1 370.1 23. ##STR52##
1-(4-methoxyphenethyl)-3-(1- methylpiperidin-4-yl)urea 291.39 291.2
292.2 24. ##STR53## 1-((2,3-dihydrobenzo[b][1,4]dioxin-
6-yl)methyl)-3-(1-methylpiperidin-4- yl)urea 305.38 305.2 306.2 25.
##STR54## 1-(3,4-dimethoxyphenethyl-3-(1- methylpiperidin-4-yl)urea
321.42 321.2 322.2 26. ##STR55## 1-(2-(1H-indol-3-yl)ethyl)-3-(1-
methylpiperidin-4-yl)urea 300.4 300.2 301.2 27. ##STR56##
1-(3-chlorobenzyl)-3-(1- methylpiperidin-4-yl)urea 281.79 281.1
282.1 28. ##STR57## 1-(3,4-dimethoxybenzyl)-3-(1-
methylpiperidin-4-yl)urea 307.39 307.2 308.2 29. ##STR58##
1-(2,3-dimethoxybenzyl)-3-(1- methylpiperidin-4-yl)urea 307.39
307.2 308.2 30. ##STR59## 1-(1-methylpiperidin-4-yl)-3-
(thiophen-2-ylmethyl)urea 253.37 253.1 254.1 31. ##STR60##
1-(3,5-dimethoxybenzyl)-3-(1- methylpiperidin-4-yl)urea 307.39
307.2 308.2 32. ##STR61## 1-(1-methylpiperidin-4-yl)-3-(4-
(trifluoromethoxy)benzyl)urea 331.34 331.2 332.2 33. ##STR62##
1-(benzo[d][1,3]dioxol-5-ylmethyl)- 3-(1-methylpiperidin-4-yl)urea
291.35 291.2 292.2 34. ##STR63## 1-(2-chloro-6-fluorobenzyl)-3-(1-
methylpiperidin-4-yl)urea 299.78 299.1 300.1 35. ##STR64##
1-((5-methylfuran-2-yl)methyl)-3-(1- methylpiperidin-4-yl)urea
251.33 251.2 252.2 36. ##STR65## 1-(2,3-dichlorobenzyl)-3-(1-
methylpiperidin-4-yl)urea 316.23 315.1 316.1 37. ##STR66##
1-(2,5-dichlorobenzyl)-3-(1- methylpiperidin-4-yl)urea 316.23 315.1
316.1 38. ##STR67## 1-(3,5-dichlorobenzyl)-3-(1-
methylpiperidin-4-yl)urea 316.23 315.1 316.1 39. ##STR68##
1-(2-methoxybenzyl)-3-(1- methylpiperidin-4-yl)urea 277.37 277.2
278.2 40. ##STR69## 1-(1-methylpiperidin-4-yl)-3-(2-
phenoxyethyl)urea 277.37 277.2 278.2 41. ##STR70##
1-(3-chloro-4-methylbenzyl)-3-(1- methylpiperidin-4-yl)urea 295.81
295.1 296.2 42. ##STR71## 1-(2-chloro-6-phenoxybenzyl)-3-(1-
methylpiperidin-4-yl)urea 373.88 373.2 374.2 43. ##STR72##
1-(2,5-dimethoxybenzyl)-3-(1- methylpiperidin-4-yl)urea 307.39
307.2 308.2 44. ##STR73## 1-(2,6-dichlorobenzyl)-3-(1-
methylpiperidin-4-yl)urea 316.23 315.1 316.1 45. ##STR74##
1-(1-methylpiperidin-4-yl)-3-(2- (pyridin-4-yl)ethyl)urea 262.36
262.2 263.2 46. ##STR75## 1-(2-(1-isopropyl-1H-imidazol-4-
yl)ethyl)-3-(1-methylpiperidin-4- yl)urea 293.41 293.2 294.2 47.
##STR76## 1-(1-methylpiperidin-4-yl)-3-(2-
(trifluoromethyl)benzyl)urea 315.34 315.2 316.2 48. ##STR77##
1-(1-methylpiperidin-4-yl)-3-(3- (trifluoromethyl)benzyl)urea
315.34 315.2 316.2 49. ##STR78## 1-(1-methylpiperidin-4-yl)-3-(3-
(trifluoromethoxy)benzyl)urea 331.34 331.2 332.2 50. ##STR79##
1-(3-fluorobenzyl)-3-(1- methylpiperidin-4-yl)urea 265.33 265.2
266.2 51. ##STR80## 1-(3,4-difluorobenzyl)-3-(1-
methylpiperidin-4-yl)urea 283.32 283.1 284.2 52. ##STR81##
1-(3,5-difluorobenzyl)-3-(1- methylpiperidin-4-yl)urea 283.32 283.1
284.2 53. ##STR82## 1-(2-methylbenzyl)-3-(1-
methylpiperidin-4-yl)urea 261.37 261.2 262.2 54. ##STR83##
1-(4-methylbenzyl)-3-(1- methylpiperidin-4-yl)urea 261.37 261.2
262.2 55. ##STR84## 1-(2-ethoxybenzyl)-3-(1-
methylpiperidin-4-yl)urea 291.39 291.2 292.2 56. ##STR85##
1-(furan-2-ylmethyl)-3-(1- methylpiperidin-4-yl)urea 237.3 237.1
238.2 57. ##STR86## 1-(4-chlorobenzyl)-3-(1-
methylpiperidin-4-yl)urea 281.79 281.1 282.1 58. ##STR87##
1-(2-chlorobenzyl)-3-(1- methylpiperidin-4-yl)urea 281.79 281.1
282.1 59. ##STR88## 1-(1-methylpiperidin-4-yl)-3-(2-
(pyridin-2-yl)ethyl)urea 262.36 262.2 263.2 60. ##STR89##
1-(1-methylpiperidin-4-yl)-3-(pyridin- 2-ylmethyl)urea 248.33 248.2
249.2 61. ##STR90## 1-(3-methoxybenzyl)-3-(1-
methylpiperidin-4-yl)urea 277.37 277.2 278.2 62. ##STR91##
1-(4-methoxybenzyl)-3-(1- methylpiperidin-4-yl)urea 277.37 277.2
278.2 63. ##STR92## 1-(3-chloro-4-methoxyphenyl)-3-(1-
methylpiperidin-4-yl)urea 297.78 297.1 298.1 64. ##STR93##
1-(2-chloro-5-methoxyphenyl)-3-(1- methylpiperidin-4-yl)urea 297.78
297.1 298.1 65. ##STR94## 1-(1-methylpiperidin-4-yl)-3-(4-
(piperidin-1-yl)phenyl)urea 316.45 316.2 317.2 66. ##STR95##
1-(1-methylpiperidin-4-yl)-3-(5- methylthiazol-2-yl)urea 254.36
254.1 255.1 67. ##STR96## 1-(4-(1,2,3-thiadiazol-4-yl)phenyl)-
3-(1-methylpiperidin-4-yl)urea 317.42 317.1 318.1 68. ##STR97##
1-(1-methylpiperidin-4-yl)-3-(2- (methylthio)benzo[d]thiazol-6-
yl)urea 336.48 336.1 337.1 69. ##STR98##
1-(3,5-dimethylpyrazin-2-yl)-3-(1- methylpiperidin-4-yl)urea 263.34
263.2 264.2 70. ##STR99## 4-(4-chlorophenyl)-4-hydroxy-N-(1-
methylpiperidin-4-yl)piperidine-1- carboxamide 351.88 351.2 352.2
71. ##STR100## 4-hydroxy-N-(1-methylpiperidin-4-
yl)-4-phenylpiperidine-1- carboxamide 317.43 317.2 318.2 72.
##STR101## 3-(benzhydryloxy)-N-(1-
methylpiperidin-4-yl)piperidine-1- carboxamide 407.56 407.3 408.3
73. ##STR102## 4-cinnamyl-N-(1-methylpiperidin-4-
yl)piperazine-1-carboxamide 342.48 342.2 343.2 74. ##STR103##
N-(1-methylpiperidin-4-yl)-4- (1,2,3,4-tetrahydronaphthalen-1-
yl)piperazine-1-carboxamide 356.51 356.3 357.3 75. ##STR104##
4-(isoquinolin-5-ylsulfonyl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 417.53 417.2 418.2
76. ##STR105## 3-methyl-N-(1-methylpiperidin-4-yl)-
4-m-tolylpiperazine-1-carboxamide 330.47 330.2 331.2 77. ##STR106##
N-(1-methylpiperidin-4-yl)-4-m- tolylpiperazine-1-carboxamide
316.45 316.2 317.2 78. ##STR107## 4-(1H-indol-3-yl)-N-(1-
methylpiperidin-4-yl)piperidine-1- carboxamide 340.47 340.2 341.2
79. ##STR108## N-(1-methylpiperidin-4-yl)-4-(6-
methylpyridin-2-yl)piperazine-1- carboxamide 317.43 317.2 318.2 80.
##STR109## 4-(3,4-dimethylphenyl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 330.47 330.2 331.2
81. ##STR110## N-(1-methylpiperidin-4-yl)-4-(1-
phenylethyl)piperazine-1- carboxamide 330.47 330.2 331.2
82. ##STR111## N-(1-methylpiperidin-4-yl)-4-
(pyridin-4-ylmethyl)piperazine-1- carboxamide 317.43 317.2 318.2
83. ##STR112## 4-(2-hydroxyphenyl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 318.42 318.2 319.2
84. ##STR113## 4-(2,4-dimethylphenyl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 330.47 330.2 331.2
85. ##STR114## N-(1-methylpiperidin-4-yl)-4-(2-
(methylthio)phenyl)piperazine-1- carboxamide 348.51 348.2 349.2 86.
##STR115## 3-hydroxy-N-(1-methylpiperidin-4-
yl)-3-phenylpiperidine-1- carboxamide 317.43 317.2 318.2 87.
##STR116## 4-(benzo[d]thiazol-2-yl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 359.5 359.2 360.2
88. ##STR117## N-(1-methylpiperidin-4-yl)-4-
tosylpiperazine-1-carboxamide 380.51 380.2 381.2 89. ##STR118##
4-(4-fluorophenylsulfonyl)-N-(1- methylpiperidin-4-yl)piperazine-1-
carboxamide 384.47 384.2 385.2 90. ##STR119##
1-(1-methylpiperidin-4-yl)-3- (5,6,7,8-tetrahydronaphthalen-1-
yl)urea 287.4 287.2 288.2 91. ##STR120##
1-(4-methoxy-2-methylphenyl)-3-(1- methylpiperidin-4-yl)urea 277.37
277.2 278.2 92. ##STR121## methyl 3-(3-(1-methylpiperidin-4-
yl)ureido)benzoate 291.35 291.2 292.2 93. ##STR122##
1-(2,4-difluorophenyl)-3-(1- methylpiperidin-4-yl)urea 269.29 269.1
270.1 94. ##STR123## 4-(2-methoxyphenyl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 332.45 332.2 333.2
95. ##STR124## 4-(4-methoxyphenylsulfonyl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 396.51 396.2 397.2
96. ##STR125## N-(1-methylpiperidin-4-yl)-4-(4-
nitrophenyl)piperazine-1- carboxamide 347.42 347.2 348.2 97.
##STR126## 4-(3,5-dichloropyridin-4-yl)-N-(1-
methylpiperidin-4-yl)piperazine-1- carboxamide 372.3 371.1 372.1
98. ##STR127## 4-benzyl-N-(1-methylpiperidin-4-
yl)piperidine-1-carboxamide 315.46 315.2 316.2 99. ##STR128##
4-(4-chlorophenyl)-N-(1- methylpiperidin-4-yl)piperazine-1-
carboxamide 336.87 336.2 337.2 100. ##STR129##
4-(2-chlorophenyl)-N-(1- methylpiperidin-4-yl)piperazine-1-
carboxamide 336.86 336.2 337.2 101. ##STR130##
3-((1H-pyrrol-1-yl)methyl)-N-(1- methylpiperidin-4-yl)piperidine-1-
carboxamide 304.44 304.2 305.2 *High Resolution analytical MS
method: Data were acquired in positive ion electrospray mode on an
electrospray orthogonal time-of-flight mass spectrometer at a
resolution of about 6500. Measurements were made with reversed
phase HPLC sample introduction using a linear ACN/water gradient
with 0.1% formic acid as the modifier. The experiment was performed
using the lockspray accessory with reserpine as the lock mass
compound.
In addition, the procedure of Example 1 may be used to prepare all
the compounds described earlier in the present specification.
* * * * *